Chemistry and Pharmacological Studies of 3-Alkoxy-2,5-Disubstituted-Pyridinyl Compounds as Novel Selective α4β2 Nicotinic Acetylcholine Receptor Ligands That Reduce Alcohol Intake in Rats

被引：12

作者：

Liu, Yong ^{[1
]}

Richardson, Janell ^{[2
]}

Thao Tran ^{[2
]}

Al-Muhtasib, Nour ^{[2
]}

Xie, Teresa ^{[2
]}

Yenugonda, Venkata Mahidhar ^{[1
]}

Sexton, Hannah G. ^{[3
]}

Rezvani, Amir H. ^{[3
]}

Levin, Edward D. ^{[3
]}

Sahibzada, Niaz ^{[2
]}

Kellar, Kenneth J. ^{[2
]}

Brown, Milton L. ^{[1
]}

Xiao, Yingxian ^{[2
]}

Paige, Mikell ^{[1
]}

机构：

[1] Georgetown Univ, Med Ctr, Ctr Drug Discovery, Washington, DC 20057 USA

[2] Georgetown Univ, Sch Med, Dept Physiol & Pharmacol, Washington, DC 20057 USA

[3] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 07期

关键词：

PARTIAL AGONISTS VARENICLINE; SUSTAINED-RELEASE BUPROPION; SAZETIDINE-A; SMOKING-CESSATION; ETHANOL-CONSUMPTION; BINDING-SITES; REINFORCING PROPERTIES; CHOLINERGIC-RECEPTOR; DESENSITIZING AGENT; ATTENUATES ALCOHOL;

D O I：

10.1021/jm4000374

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Neuronal acetylcholine receptors mediate the addictive effects of nicotine and may also be involved in alcohol addiction. Varenicline, an approved smoking cessation medication, showed clear efficacy in reducing alcohol consumption in heavy-drinking smokers. More recently, sazetidine-A, which selectively desensitizes alpha 4 beta 2 nicotinic receptors, was shown to significantly reduce alcohol intake in a rat model. To develop novel therapeutics for treating alcohol use disorder, we designed and synthesized novel sazetidine-A analogues containing a methyl group at the 2-position of the pyridine ring. In vitro pharmacological studies revealed that some of the novel compounds showed overall pharmacological property profiles similar to that of sazetidine-A but exhibited reduced agonist activity across all nicotinic receptor subtypes tested. In rat studies, compound (S)-9 significantly reduced alcohol uptake. More importantly, preliminary results from studies in a ferret model indicate that these novel nAChR ligands have an improved adverse side-effect profile in comparison with that of varenicline.

引用

页码：3000 / 3011

页数：12